SPIRONOLACTONE 100 UNICORN

Indications

• Heart failure
• Hypertension
• Edema associated with liver cirrhosis
• Nephrotic syndrome
• Primary hyperaldosteronism

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: Initially 100–200 mg daily, then increased if necessary to a maximum of 400 mg daily, adjusted according to response.

Mechanism of action

Spironolactone and its active metabolites bind competitively to the mineralocorticoid receptor in the distal convoluted renal tubule, antagonizing aldosterone's effects. This leads to increased sodium and water excretion while retaining potassium. Additionally, spironolactone has antiandrogenic effects, reducing testosterone synthesis and impacting androgen receptor activity.

Pharmacodynamics

Spironolactone promotes diuresis while sparing potassium, which is crucial for maintaining electrolyte balance. It raises renin and aldosterone levels, while also demonstrating progestogenic and anti-androgenic properties. The drug exhibits anti-inflammatory effects and has low affinity for glucocorticoid receptors, making it suitable for managing fluid retention without causing significant potassium loss.

Pharmacokinetics

Spironolactone is well-absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1 to 3 hours post-administration. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes, resulting in active metabolites. The drug has a half-life of about 1.4 hours, but its effects can last longer due to its active metabolites. Renal clearance is significant, and dosage adjustments may be necessary in patients with renal impairment.

Contra-indications

• Severe renal impairment
• Acute renal insufficiency
• Hyperkalaemia

Adverse effects

• Hyperkalaemia
• Acidosis
• Agranulocytosis
• Alopecia
• Breast neoplasm benign
• Breast pain
• Confusion
• Dizziness
• Electrolyte imbalance
• Gastrointestinal disorder
• Gynaecomastia
• Hepatic function abnormality
• Hypertrichosis
• Leg cramps
• Leucopenia
• Libido disorder
• Malaise
• Menstrual disorder
• Nausea
• Severe cutaneous adverse reactions
• Skin reactions
• Thrombocytopenia

Interactions

• Digoxin (increases concentration)
• Lithium (unknown, may increase concentration)
• Mitotane (unknown, may decrease effects)

Precautions

• Monitor potassium levels before treatment, during initiation, and after any dose changes
• Use with caution in renal impairment, low blood pressure, ischaemic heart disease, and diffuse vascular disease
• Consider potential risks during pregnancy and breastfeeding

Pregnancy

Use only if potential benefit outweighs risk; concerns about feminisation of male fetus in animal studies.

Breast-feeding

Metabolites present in milk, but the amount is probably too small to be harmful.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets (25 mg, 50 mg, 100 mg)
• Oral suspension
• Solution for injection

Mechanism of action

Aldosterone is a key hormone in the renin-angiotensin-aldosterone system. By binding to the mineralocorticoid receptor at the distal tubules and collecting duct, it causes sodium reabsorption and potassium secretion, increases vascular stiffness and remodelling, and activates pro-inflammatory pathways. Spironolactone and its active metabolites are aldosterone antagonists that produce a potassium-sparing diuretic effect. They competitively bind to receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents that act more proximally in the renal tubule. Spironolactone can exert antiandrogenic effects by several mechanisms: it can destroy testicular CYP and decrease 17alpha-hydroxylase activity, resulting in decreased testosterone synthesis; and it can inhibit 5alpha-dihydrotestosterone binding to cytosolic androgen receptor in the prostate. Spironolactone exhibits antiandrogenic effects in males and females. The mechanism of antiandrogenic activity of spironolactone is complex and appears to involve several effects of the drug. Spironolactone decreases testosterone biosynthesis by inhibiting steroid 17alpha-monooxygenase (17alpha-hydroxylase) activity, possibly secondary to destruction of microsomal cytochrome P-450 in tissues with high steroid 17alpha-monooxygenase activity (e.g., testes, adrenals). The drug also appears to competitively inhibit binding of dihydrotestosterone to its cytoplasmic receptor protein, thus decreasing androgenic actions at target tissues. Spironolactone-induced increases in serum estradiol concentration also may contribute to its antiandrogenic activity, although such increases may not occur consistently; such increases appear to result from increased conversion of testosterone to estradiol. Spironolactone may have variable effects on serum 17-hydroxyprogesterone concentrations, possibly decreasing its production by inhibiting steroid 17alpha-monooxygenase activity or decreasing its conversion (with resultant accumulation) to androstenedione by inhibiting cytochrome P450-dependent 17alpha-hydroxyprogesterone aldolase (17,20-desmolase) activity. Serum progesterone concentrations may increase with the drug secondary to decreased hydroxylation (via steroid 17alpha-monooxygenase) to 17-hydroxyprogesterone. In children, compensatory increases in lutropin (luteinizing hormone, LH) and follicle-stimulating hormone (FSH) secretion can occur, probably secondary to the drug's antiandrogenic effects (i.e., a feedback response to decreasing serum testosterone concentrations and/or peripheral androgenic activity). MEDICATION (VET): Spironolactone is used most frequently and is a competitive antagonist of aldosterone. Aldosterone is elevated in animals with congestive heart failure in which the renin-angiotensin system is activated in response to hyponatremia, hyperkalemia, and reductions in blood pressure or cardiac output. Aldosterone is responsible for increasing sodium and chloride reabsorption and potassium and calcium excretion from renal tubules. Spironolactone competes with aldosterone at its receptor site, causing a mild diuresis and potassium retention. High concentrations of spironolactone have been reported to interfere with steroid biosynthesis by inhibiting 11 beta- and 18-, 21-, and 17 alpha-hydroxylase.

Pharmacodynamics

Spironolactone has a potassium-sparing diuretic effect. It promotes sodium and water excretion and potassium retention. It increases renin and aldosterone levels. Spironolactone is a mineralocorticoid receptor antagonist and has a low affinity for the glucocorticoid receptor. It also exhibits progestogenic and anti-androgenic actions as it binds to the androgen receptor and, to a lesser extent, estrogen and progesterone receptors. Spironolactone exhibits anti-inflammatory effects.